In this article, we try to summarize the most important novel biological information on the complex interrelationships between acid-base alterations and hypoxia-inducible factor (HIF) signaling. Extracellular and intracellular acid-base alterations affect HIF signaling in part independently of hypoxia, and involve, among others, effects on cytoprotection and apoptosis. Conversely, HIF signaling may affect systemic and local acid production rates and has been implicated in the mechanism of the acute hyperventilatory response (ie, respiratory alkalosis) in response to hypoxia as well as for hypoxia-induced pulmonary artery hypertension (PAH), although the latter data are quite preliminary and can be explained by alternative mechanisms. Thus, this review calls attention to these relationships for renal physiologists and nephrologists to stimulate focused clinical observations and specific investigative efforts as proposed in this overview.